The long-term goal of this project is to determine the mechanisms by which the peroxisome proliferator-activated receptor (PPAR)-gamma modulates inflammatory diseases of the central nervous system (CNS), including multiple sclerosis (MS). The critical role of PPAR-gamma in glucose and lipid metabolism is well established. Recently, however, PPAR-gamma was also demonstrated to be a potent inhibitor of macrophage activation. Our studies indicated that PPAR-gamma ligands inhibited the activation of microglia in response to interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, cytokines that may contribute to the pathology associated with MS. In addition, PPAR-gamma is expressed by T cells and affects T-cell proliferation. PPAR-gamma ligands also indirectly affect T-cell function by inhibiting the production of T-cell active chemokines by endothelial cells. Importantly, PPAR-gamma ligands have recently been demonstrated to ameliorate a variety of inflammatory conditions, including arthritis, atherosclerosis, and inflammatory bowel disease. We have recently demonstrated that a PPAR-gamma ligand blocks the development of experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Collectively, these studies suggest that PPAR-gamma ligands may be efficacious in the treatment of MS. The mechanisms by which PPAR-gamma ligands modulate susceptibility to MS have not been elucidated. MS is believed to be initiated by autoreactive T cells. Activated microglia also contribute to MS development through production of a variety of molecules that may affect the viability of myelin-producing oligodendrocytes, and are capable of altering T-cell phenotype. The hypothesis of the proposed studies is that PPAR-gamma agonists (1) inhibit the activation of microglia resulting in protection of oligodendrocytes, (2) inhibit microglial production of chemokine and chemokine receptors believed to contribute to the movement of immune cells into the CNS in MS patients, (3) affect T-cell phenotype and apoptosis, and (4) inhibit the development of EAE.